Itraconazole compositions with improved bioavailability

ABSTRACT

A solid dispersion product comprising itraconazole and hydroxypropyl methylcellulose, which satisfies the Formula 0.35&gt;ΔH tr  (1) (wherein ΔH tr  represents the endotherm (J/g) accompanying a transition at about 240° C.). The solid dispersion product shows an improved bioavailability.

This application is a divisional application of U.S. application Ser.No. 11/997,256, now U.S. Pat. No. 8,486,456, which is the U.S. nationalphase, pursuant to 35 U.S.C. §371, of PCT international application Ser.No. PCT/EP2006/007839, filed Aug. 8, 2006, designating the United Statesand published in English on Feb. 15, 2007 as publication WO 2007/017248A2, which claims priority to U.S. provisional patent application Ser.No. 60/595,816, filed Aug. 8, 2005. The entire contents of theaforementioned patent applications are incorporated herein by thisreference.

The present invention relates to novel pharmaceutical compositions ofitraconazole as well as to a process for their preparation. Thedevelopment of pharmaceutical compositions having good bioavailabilityof itraconazole, a compound that is practically insoluble in aqueousmedia, remains one of the main challenges of pharmaceutical developmentof this compound. Itraconazole or(+)-cis-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-{1H-1,2,4-triazol-1-yl-methyl)-1,3-dioxoian-4-yl]methoxy]phenyl]-1-piperazinyljphenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one,is a broadspectrum antifungal compound developed for oral, parenteraland topical use and is disclosed in U.S. Pat. No. 4,267,179.

WO 97/44014 discloses an itraconazole composition that comprisesparticles which are obtainable by melt-extruding a mixture comprisingitraconazole and an appropriate water-soluble polymer, such ashydroxypropyl methylcellulose, and subsequently milling themelt-extruded mixture. These compositions exhibited an improvedbioavailability of itraconazole over the oral dosage forms ofitraconazole known at the time.

Nevertheless, it is desirable to provide dosage forms of itraconazolewith still greater bioavailability. This objective is met by a soliddispersion product comprising itraconazole and hydroxypropylmethylcellulose, which satisfies the formula0.35>ΔH_(tr)(wherein AH_(tr) represents the endotherm (J/g) accompanying atransition at an endothermic peak temperature in the range of from about240° C. to about 250° C.).

Preferably, the solid dispersion product satisfies the formula0.20>ΔH_(tr)

More preferably, the solid dispersion product satisfies the formula0.15>ΔH_(tr)

The ΔH_(tr) is determined by differential scanning calorimetry (DSC)measurement. More specifically, a melting endotherm curve is firstprepared by the following method using a differential scanningcalorimeter. A finely ground sample of the dispersion product is placedin an open aluminium pan of a differential scanning calorimeter. Theendotherm between −20° C. and 300° C. is obtained by heating the sampleat a temperature rise rate of 10° C./minute. A maximum peak is observedin the thus prepared melting endotherm curve in the range of from about240° C. to about 250° C. (in the following also referred to as“endotherm at about 240° C.”), and the change rate of enthalpy observedthereupon, in terms of Joules per one gram of solid dispersion product,is determined to be the endotherm AH_(tf). The change rate of enthalpycorresponds to the area enclosed between the peak and the interpolatedbase line.

The invention further relates to a pharmaceutical dosage form comprisinga solid dispersion product of itraconazole and hydroxypropylmethylcellulose, the dosage form providing in vivo plasma levels ofitraconazole and hydroxy itraconazole (combined) characterized byC_(max) of 400 ng/mL or higher, preferably 450 ng/mL or higher, afteroral administration of a single dose of 200 mg itraconazole. “C_(max)”designates the peak plasma concentration observed after oraladministration to a human. Itraconazole and hydroxy itraconazole levelsin the plasma may be assessed by any art-accepted method.

The term “solid dispersion” defines a system in a solid state (asopposed to a liquid or gaseous state) comprising at least twocomponents, wherein one component is dispersed more or less evenlythroughout the other component or components. When said dispersion ofthe components is such that the system is chemically and physicallyuniform or homogenous throughout or consists of one phase (as defined inthermodynamics), such a dispersion is called a “solid solution”. Solidsolutions are preferred physical systems because the components thereinreadily form liquid solutions when brought into contact with a liquidmedium such as gastric juice. This increased propensity for dissolutionmay be attributed at least in part to the fact that the energy requiredfor dissolving the components from a solid solution is less than thatrequired for dissolving the components from a crystalline ormicrocrystalline solid phase.

The term “solid dispersion product” also comprises dispersions which areless homogeneous throughout than solid solutions. Such dispersions arenot chemically and physically uniform throughout or comprise more thanone phase. These encompass systems having small particles, typically ofless than 1 ^m in diameter, of itraconazole dispersed in a matrix ofhydroxypropyl methylcellulose, as well as systems having small particlesof itraconazole dispersed in a matrix of a solid solution ofitraconazole in hydroxypropyl methylcellulose. Preferred systems arethose wherein the itraconazole is in an essentially non-crystallinephase as these have an intrinsically faster dissolution rate than thosewherein part or all of the itraconazole is in a microcrystalline orcrystalline form. The absence of microcrystalline or crystallineitraconazole forms may be ascertained by thermal analysis (DSC) or X-raydiffraction analysis (WAXS).

Without wishing to be bound to theory, we believe that polymer “melting”from a crystalline state to nematic “liquid” state generally uses aroute which includes a passage via a mesomorphic (liquid crystalline)phase. If the starting hydroxypropyl methylcellulose is incompletely“molten” some mesomorphic domains remain in the polymeric matrix.

We believe that the mesomorphic domains have thermodynamic propertieswhich place them intermediate between melt and crystals and, hence, theendotherm observed at about 240° C. is attributable to the latent heatof transition, i.e., the melting of the mesomorphic domains. The lowerthe change rate of enthalpy, the lower the proportion of mesomorphicdomains in the formulation and the more homogeneous the polymericmatrix. High bioavailability appears to be linked to a highlyhomogeneous matrix.

Four diastereoisomers of itraconazole exist, the preparation and utilityof which are disclosed in WO 93/19061. The preferred itraconazolecompound is the (±)-(2R*,4S*) or cis forms of the free base, having theChemical Abstracts Registry Number [8462561-6], The term “itraconazole”as used herein shall include any of its stereoisomers or a mixture oftwo or three or four of its stereoisomers.

Instead of the itraconazole free base, acid addition salts thereof maybe used. The acid addition salts may be obtained by reacting the freebase with an appropiate acid. Appropiate acids may include, for example,inorganic acids such as hydrohalic acids, e.g. hydrochloric orhydrobromic acid, sulfuric acid; nitric acid; phosphoric acid and thelike; or organic acids such as, for example, formic, acetic, propanoic,hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic,propanediol, butanedioic, (Z)-butanedioic, (E)-butanedioic,2-hydroxybutanedioic, 2,3-dihydroxybutanedioic,2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic,benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfonic,2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and like acids.

The hydroxpropyl methylcellulose (HPMC) used in carrying out theinvention contains a sufficient number of hydroxypropyl and methoxygroups to render it water-soluble.

The total content of methoxy and hydroxypropyl groups is preferably inthe range of 23 to 42% by weight. More preferably, the total content ofmethoxy and hydroxypropyl groups is in the range of 30 to 42% by weight.Preferably, the methoxy group content is in the range of 19 to 30 wt %(in particular 28 to 30 wt %) and the hydroxypropyl group content is inthe range of 4 to 12 wt % (in particular 7 to 12 wt %).

Hydroxypropyl methylcellulose is also known as hypromellose (seeMartindaie, The Extra Pharmacopoeia, 29^(th) edition (PharmaceuticalPress, 1989) page 1435). For HPMC, three types are commerciallyavailable: HPMC 2208, HPMC 2906, and HPMC 2910, depending on thecontents of methoxy and hydroxypropyl groups. In the four digit numberassociated with HPMC as described by Martindale, the first two digitsrepresent the approximate percentage of methoxy groups and the third andfourth digits the approximate percentage composition of hydroxypropylgroups, it is specified that hydroxypropyl methyl cellulose 2208contains 19 to 24 wt % of methoxy groups and 4 to 12 wt % ofhydroxypropyl groups in a total of 23 to 36 wt %; hydroxypropyl methylcellulose 2906 contains 27 to 30 wt % of methoxy groups and 4 to 7.5 wt% of hydroxypropyl groups in a total of 31 to 37.5 wt %, andhydroxypropyl methyl cellulose 2910 contains 28 to 30 wt % of methoxygroups and 7 to 12 wt % of hydroxypropyl groups in a total of 35 to 42wt %. Any of these celluloses may be used in the practice of theinvention, with HPMC 2910 being especially preferred.

The molecular weight of the HPMC normally affects both the releaseprofile of the milled extrudate as well as its physical properties. Adesired release profile can thus be designed by choosing an HPMC of anappropriate molecular weight. For immediate release of the activeingredient from the particles, a low molecular weight polymer ispreferred. A high molecular weight HPMC is more likely to yield asustained release pharmaceutical dosage form. The molecular weight of awater-soluble cellulose ether, such as HPMC, is generally expressed interms of the apparent viscosity of an aqueous solution containing twopercent by weight of said cellulose ether at 20° C. Suitable HPMCsinclude those having a viscosity from about 1 to about 100 mPa·s, morepreferably from about 3 to about 15 mPa·s, and most preferably at about5 mPa·s. The most preferred type of HPMC having a viscosity of 5 mPa·sis the commercially available HPMC 2910 5 mPa·s.

Although it is believed that the particle size distribution of the HPMCstarting material is of secondary influence to the properties of soliddispersion product, the HPMC starting material preferably has a sizedistribution (as determined using laser light diffraction; MalvernMastersizer) with d₀.5 of not more than 125 (and, more preferably of notmore than 100. Preferably, d₀.g is not more than 300 ^m, more preferablynot more than 245 (jm.

Preferably, the weight ratio of itraconazole:hydroxypropylmethylcellulose is in the range of 1:1 to 1:17, more preferably 1:1 to1:5, In the case of (itraconazole):(HPMC 2910 5 mPa·s), this ratio mayrange from about 1:1 to about 1:2 and is optimally about 1:1.5 (or 2:3).The lower limit is determined by practical considerations, indeed, giventhat the therapeutically effective amount of itraconazole is from about50 mg to about 400 mg per day, preferably 200 mg per day, the lowerlimit ratio is determined by the maximum amount of mixture that can beprocessed into one dosage form of a practical size. When the relativeamount of water-soluble polymer exceeds the upper acceptable range, theabsolute amount of mixture needed to achieve a therapeutic level will betoo great to be processed into one capsule or tablet. Tablets, forexample, can have a maximum weight of about 1 gram, of which a maximumof 90% (w/w) can be the extrudate. In this case, the lower limit of theamount of itraconazole compared to hydroxypropyl methylcellulose will beabout 1:17 (i.e., 50 mg itraconazole and 50 mg polymer).

As the ratio of itraconazole:hydroxypropyl methylcellulose increases(i.e. the amount of itraconazole increases relative to the amount ofpolymer), then there is the risk that the itraconazole will not dissolvesufficiently in the polymer and thus that the required bioavailabilitywill not be obtained. The degree to which a compound has dissolved in awater-soluble polymer can often be checked visually. If the extrudate isclear, then it is likely that the compound has dissolved completely inthe water-soluble polymer. The 1:1 itraconazole:hydroxypropylmethylcellulose upper limit is determined by the fact that it has beenobserved that, at this ratio, the extrudate resulting from extrudingitraconazole with HPMC 2910 5 mPa·s was not “clear”, presumably due tothe fact that not all of the itraconazole had dissolved in the HPMC. Itwill be appreciated that the upper limit of 1:1 may be an underestimatefor other types of HPMC.

The solid dispersion product of the invention is prepared by amelt-extrusion process.

The melt-extrusion process typically comprises the following steps:

a) blending itraconazole and hydroxypropyl methylcellulose;

b) heating the blend to obtain a homogenous melt,

c) forcing the thus obtained melt through one or more nozzles; and

d) allowing the melt to solidify to obtain a solid dispersion product.

Specifically, the method comprises the following steps:

a) blending itraconazole and a hydroxypropyl methylcellulose or amixture of two or more hydroxypropyl methylcelluloses;

b) heating the blend, under preset conditions of temperature, shear andthroughput rate, to obtain a homogeneous melt;

c) forcing the thus obtained melt through one or more nozzles;

d) allowing the melt to solidify to obtain a solid dispersion product;

e) subjecting a representative sample of the obtained solid dispersionproduct to differential scanning calorimetry measurement; and, ifnecessary,

f) adjusting the conditions of temperature, shear and throughput rateused in step b) such that the solid dispersion product satisfies theformula0.35>ΔH_(tr),

-   -   preferably 0.20>ΔH_(tr),    -   more preferably 0.15>ΔH_(t),        (wherein ΔH_(tf) represents the endotherm (J/g) accompanying a        transition at an endothermic peak temperature in the range of        from about 240° C. to about 250° C.

The terms “melt” and “melting” should be interpreted broadly. For ourpurposes, these terms not only mean the alteration from a solid state toa liquid state, but can also refer to a transition to a glassy state ora rubbery state, and in which it is possible for one component of themixture to get embedded more or less homogeneously into the other. Inparticular cases, one component will melt and the other component(s)will dissolve in the melt thus forming a solution, which, upon cooling,may form a solid solution having advantageous dissolution properties.

The melting and/or mixing takes place in an apparatus customarily usedfor this purpose. Particularly suitable are extruders or kneaders.Suitable extruders include single screw extruders, intermeshing screwextruders or else multiscrew extruders, preferably twin screw extruders,which can be corotating or counterrotating and are optionally equippedwith kneading disks. The heart of any twin-screw compounding extruder isits screws. Typically, the screws comprise forward-flighted elements toconvey the materials; further, they may comprise reverse-flightedelements to create pressure fields, and kneaders and shear elements toexert a kneading action to the melt. Screws can be made shear intensiveor less aggressive based on the number and type of shearing elementsintegrated into the screw program.

The melt ranges from pasty to viscous. Before allowing the melt tosolidify, the melt may be moulded into virtually any desired shape. Theshaping of the extrudate is conveniently carried out by a calender withtwo counter-rotating rollers with mutually matching depressions on theirsurface. A broad range of tablet forms can be attained by using rollerswith different forms of depressions. Alternatively, the extrudate is cutinto pieces, either before (hot-cut) or after solidification (cold-cut).

In one embodiment the melt is extruded through a slot die to obtain afilm. The film thus obtained is optionally stretched, axially orbiaxially. The film can be cut into the desired size.

It has been found that the energy input during melt-extrusion productionis important for good bioavailability. Based upon the results of theexamples that follow, it is postulated that the higher the energy inputin the extrusion process, the better the dispersion of itraconazole inthe matrix. A lower endotherm at 240° C. is indicative of betterdispersion.

One of the most important parameters governing energy input during themelt-extrusion process is the temperature at which the melt-extruder isoperating and the temperature at which the nozzle, through which themelt is forced, is kept. The temperature may vary along the length ofthe extruder barrel. For the purposes herein, the “operatingtemperature” is the highest temperature the mixture encounters duringits passage through the extruder. It was found that the operatingtemperature should range between about 195° C. and about 300° C. Attemperatures lower than 195° C., the extrudate will not have therequired bioavailability. In addition, the process is difficult becauseof the high viscosity of the mixture. At temperatures of more than 300°C. the hydroxypropyl methylcellulose may decompose to an unacceptablelevel. It should be noted that there is no need to fear decomposition ofitraconazole at temperatures up to 300° C., since this active ingredientis thermally very stable. The working temperatures will also bedetermined by the kind of extruder or the kind of configuration withinthe extruder that is used.

The throughput rate is also of importance. The longer the mixtureremains in contact with the heating element, the higher the energyinput. Although most of the energy needed to melt, mix and dissolve thecomponents in the extruder is usually provided by the heating elements,the friction of the material within the extruder may also provide asubstantial amount of energy to the mixture and aid in the formation ofa homogenous melt of the components. Thus, variation of the screw speedof the extruder has an impact on the energy input. We have found thattypically a screw speed of more than 80 revolutions per minute,preferably of more than 100 revolutions per minute up to 350 revolutionsper minute, is required to bring about sufficient mixing and shearing.

In the method of the invention it is preferred that the melt issubjected to a kneading action in a kneading section of the extruder.The kneading section may be equipped with kneading disks or rotorblades.

It will be appreciated that, based on the explanation above and theexamples that follow, the person skilled in the art will be able toselect appropriate parameters for the melt extrusion process to produceextrudates that satisfy the above formula pertaining to ΔH_(tr).

The solid dispersion product may further comprise one or morepharmaceutically acceptable excipients such as, for example,plasticizers, surfactants, flavors, colorants, preservatives and thelike. Said excipients should not be heat-sensitive, in other words, theyshould not show any appreciable degradation or decomposition at theworking temperature of the melt-extruder.

The amount of plasticizer is preferably small, in the order of 0% to 15%(w/w), preferably less than 5% (w/w). In particular, no plasticizer ispresent in the solid dispersion product. Plasticizers as mentionedhereinbelow lower the temperature at which a melt of itraconazole,hydroxypropyl methylcellulose and plasticizer is formed; this loweringof the melting point is sometimes advantageous. Suitable plasticizersare pharmaceutically acceptable and include low molecular weightpolyalcohols such as ethylene glycol, propylene glycol, 1,2-butyleneglycol, 2,3-butylene glycol, styrene glycol; polyethylene glycols suchas diethylene glycol, triethylene glycol, tetraethylene glycol; otherpolyethylene glycols having a molecular weight lower than 1,000 g/mol;polypropylene glycols having a molecular weight lower than 200 g/mol;glycol ethers such as monopropylene glycol monoisopropyl ether;propylene glycol monoethyl ether; diethylene glycol monoethyl ether;ester type plasticizers such as sorbitol lactate, ethyl lactate, butyllactate, ethyl glycolate, allyl glycollate; and amines such asmonoethanolamine, diethanolamine, triethanolamine, monoisopropanolamide;triethylenetetramine, 2-amino-2-methyl-1,3-propanediol and the like.Among these, the low molecular weight polyethylene glycols, ethyleneglycol, low molecular weight polypropylene glycols and especiallypropylene glycol are preferred.

The term “pharmaceutically acceptable surfactant” refers to apharmaceutically acceptable non-ionic surfactant. The surfactant mayeffect an instantaneous emulsification of the active ingredient releasedfrom the dosage form and prevent precipitation of the active ingredientin the aqueous fluids of the gastrointestinal tract. Preferredsurfactants are selected from: polyoxyethylene alkyl ethers, e.g.polyoxyethylene (3) lauryl ether, polyoxyethylene (5) cetyl ether,polyoxyethylene (2) stearyl ether, polyoxyethylene (5) stearyl ether;polyoxyethylene alkylaryl ethers, e.g. polyoxyethylene (2) nonylphenylether, polyoxyethylene (3) nonylphenyl ether, polyoxyethylene (4)nonylphenyl ether or polyoxyethylene (3) octylphenyl ether; polyethyleneglycol fatty acid esters, e.g. PEG-200 monolaurate, PEG-200 dilaurate,PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate or PEG-300dioleate; alkylene glycol fatty acid mono esters, e.g. propylene glycolmonolaurate (Lauroglycol®); sucrose fatty acid esters, e.g. sucrosemonostearate, sucrose distearate, sucrose monolaurate or sucrosedilaurate; sorbitan fatty acid mono esters such as sorbitan mono laurate(Span® 20), sorbitan monooleate, sorbitan monopalmitate (Span® 40), orsorbitan stearate, polyoxyethylene castor 35 oil derivates, e.g.polyoxyethyleneglycerol triricinoleate or polyoxyl 35 castor oil(Cremophor® EL; BASF Corp.) or polyoxyethyleneglycerol oxystearate suchas polyethylenglycol 40 hydrogenated castor oil (Cremophor® RH 40) orpolyethylenglycol 60 hydrogenated castor oil (Cremophor® RH 60); orblock copolymers of ethylene oxide and propylene oxide, also known aspolyoxyethylene polyoxypropylene block copolymers or polyoxyethylenepolypropyleneglycol such as Poloxamer® 124, Poloxamer® 188, Poloxamer®237, Poloxamer® 388, or Poloxamer® 407 (BASF Wyandotte Corp.); or monofatty acid esters of polyoxyethylene (20) sorbitan, e.g. polyoxyethylene(20) sorbitan monooleate (Tween® 80), polyoxyethylene (20) sorbitanmonostearate (Tween® 60), polyoxyethylene (20) sorbitan monopalmitate(Tween® 40), polyoxyethylene (20) sorbitan monolaurate (Tween® 20), ormixtures of one or more thereof.

The solid dispersion product is preferably milled or ground to particleshaving a particle size of less than 600 jam, preferably less than 400p.m and most preferably less than 125 jam. The particle size proves tobe an important factor in determining the speed at which tablets havingsufficient hardness can be manufactured on a large scale; the smallerthe particles, the higher the tabletting speed can be withoutdetrimental effects on their quality. The particle size distribution issuch that more than 70% of the particles (measured by weight) have adiameter ranging from about 50 |j.m to about 500 jj.m, in particularfrom about 50 nm to about 200 nm and especially from about 50 nm toabout 125 nm. Particles with the dimensions mentioned herein can beobtained by sieving them through nominal standard test sieves asdescribed in the CRC Handbook, 64^(th) ed., page F-114. Nominal standardsieves are characterized by the mesh/hole width (jim), DIN 4188 (mm),ASTM E 11-70 (No), Tyier(R) (mesh) or BS 410 (mesh) values. Throughoutthis description, particle sizes are designated by reference to themesh/hole width in ^m and to the corresponding Sieve No. in the ASTME11-70 standard.

Once the extrudate is obtained, it is milled and sieved and used as a“normal” ingredient to make pharmaceutical dosage forms.

The particles of the solid dispersion product can be formulated intopharmaceutical dosage forms comprising a therapeutically effectiveamount of particles. Although mainly pharmaceutical dosage forms fororal administration such as tablets and capsules are envisaged, theparticles of the present invention can also be used to preparepharmaceutical dosage forms e.g. for rectal administration. Preferreddosage forms are those adapted for oral administration shaped as atablet. They can be produced by conventional tabletting techniques withconventional ingredients or excipients and with conventional tablettingmachines, in addition, they can be produced at substantially lower costthan the coated cores. An effective antifungal daily dose ofitraconazole ranges from about 50 mg to about 300 mg o.d., and ispreferably about 200 mg o.d. Preferably, the (milled) solid dispersionproduct accounts for not less than 40 wt. % of the weight of the finaldosage form, in particular from 45 to 90 wt. %.

In order to facilitate the swallowing of such a dosage form by a mammal,it is advantageous to give the dosage form, in particular tablets, anappropriate shape. Tablets that can be swallowed comfortably aretherefore preferably elongated rather than round in shape. Especiallypreferred are biconvex oblate tablets. As discussed below in moredetail, a film coat on the tablet further contributes to the ease withwhich it can be swallowed.

Tablets that give an immediate release of itraconazole upon oralingestion and that have good bioavailability are designed in such amanner that the tablets disintegrate rapidly in the stomach (immediaterelease) while keeping the particles liberated in the process away fromone another so that they do not coalesce, create local highconcentrations of itraconazole and increase the chances that the drugprecipitates (bioavailability). The desired effect can be obtained bydistributing said particles homogeneously throughout a mixture of adisintegrant and diluent.

Suitable disintegrants are those that have a large coefficient ofexpansion. Examples thereof are hydrophilic, insoluble or poorlywater-soluble crosslinked polymers such as crospovidone (crosslinkedpolyvinylpyrrolidone) and croscarmellose (crosslinked sodiumcarboxymethylcellulose). The amount of disintegrant in immediate releasetablets according to the present invention may conveniently range fromabout 3 to about 15% (w/w) and is preferably about 7 to 9%, inparticular about 8.5% (w/w). This amount tends to be greater in tabletsin order to ensure that the particles are spread throughout a largevolume of the stomach contents upon ingestion. Because disintegrants bynature yield sustained release formulations when employed in bulk, it isadvantageous to dilute them with an inert substance called a diluent orfitter.

A variety of materials may be used as diluents or fillers. Examples arespray-dried or anhydrous lactose, sucrose, dextrose, mannitol, sorbitol,starch, cellulose (e.g. microcrystalline cellulose Avicel®), dihydratedor anhydrous dibasic calcium phosphate, and others known in the art, andmixtures thereof. A commercial spray-dried mixture of lactosemonohydrate (75%) with microcrystalline cellulose (25%), which iscommercially availble as Microcelac®, is preferred. The amount ofdiluent or filler in the tablets may conveniently range from about 20%to about 40% (w/w) and preferably ranges from about 25% to about 32%(w/w).

The tablet may include a variety of one or more other conventionalexcipients such as binders, buffering agents, lubricants, glidants,thickening agents, sweetening agents, flavors, and colors. Someexcipients can serve multiple purposes.

Lubricants and glidants can be employed in the manufacture of certaindosage forms, and will usually be employed when producing tablets.Examples of lubricants and glidants are hydrogenated vegetable oils,e.g. hydrogenated Cottonseed oil, magnesium stearate, stearic acid,sodium lauryl sulfate, magnesium lauryl sulfate, colloidal silica, talc,mixtures thereof, and others known in the art. Interesting lubricantsand glidants are magnesium stearate, and mixtures of magnesium stearatewith colloidal silica. A preferred lubricant is hydrogenated vegetableoil type I, most preferably hydrogenated, deodorized Cottonseed oil(commercially available from Karlshamns as Akofine NF® (formerly calledSterotex®). Lubricants and glidants generally comprise 0.2 to 7.0% ofthe total tablet weight.

Other excipients such as coloring agents and pigments may also be addedto the tablets of the present invention. Coloring agents and pigmentsinclude titanium dioxide and dyes suitable for food. A coloring agent isan optional ingredient in the tablet of the present invention, but, whenused, the coloring agent can be present in an amount of up to 3.5% basedon the total tablet weight.

Flavors are optional in the composition and may be chosen from syntheticflavor oils and flavoring aromatics or natural oils, extracts fromplants leaves, flowers, fruits and so forth and combinations thereof.These may include cinnamon oil, oil of wintergreen, peppermint oils, bayoil, anise oil, eucalyptus, thyme oil. Also useful as flavors arevanilla, citrus oil, including lemon, orange, grape, lime andgrapefruit, and fruit essences, including apple, banana, pear, peach,strawberry, raspberry, cherry, plum, pineapple, apricot and so forth.The amount of flavor may depend on a number of factors including theorganoleptic effect desired. Generally the flavor will be present in anamount of from about 0% to about 3% (w/w).

As known in the art, tablet blends may be dry-granulated orwet-granulated before tabletting. The tabletting process itself isotherwise standard and readily practised by moulding a tablet from adesired blend or mixture of ingredients into the appropriate shape usinga conventional tablet press.

Tablets of the present invention may further be film-coated to improvetaste or provide ease of swallowing and an elegant appearance. Manysuitable polymeric film-coating materials are known in the art. Apreferred film-coating material is hydroxypropyl methylcellulose HPMC,especially HPMC 2910 5 mPa·s. Other suitable film-forming polymers alsomay be used herein, including hydroxypropylcellulose andacrylate-methacrylate copolymers. Besides a film-forming polymer, thefilm coat may further comprise a plasticizer (e.g. propylene glycol)and, optionally, a pigment (e.g. titanium dioxide). The film-coatingsuspension also may contain talc as an anti-adhesive. In immediaterelease tablets according to the invention, the film coat is small andin terms of weight accounts for less than about 3% (w/w) of the totaltablet weight.

Preferred dosage forms are those wherein the weight of the particles isat least 40% of the total weight of the total dosage form, the weight ofthe diluent ranges from 20 to 40%, and the weight of the disintegrantranges from 3 to 10%, the remainder being accounted for by one or moreof the excipients described above.

Preferred dosage forms according to the present invention are those fromwhich at least 85% of the available itraconazole dissolves within 60minutes when a dosage form equivalent to 200 mg itraconazole is testedas set forth in USP test <711> in a USP-2 dissolution apparatus underconditions at least as stringent as the following: 900 ml phosphatebuffer, pH 6.0, 37° C. with paddles turning at 100 rpm. Tabletscomplying with the preceding definition can be said to have Q>85% (60minutes). Preferably, tablets according to the present invention willdissolve faster and have Q>85% (15 minutes), more preferably Q>85% (5minutes).

Further, this invention concerns a solid dispersion product as describedabove for use in preparing a pharmaceutical dosage form for oraladministration to a mammal suffering from a fungal infection.Preferably, a single such dosage form can be administered once daily tosaid mammal. Preferably, said dosage form can be administered at anytime of the day regardless of the food taken in by said mammal.

The present invention also concerns the use of a solid dispersionproduct as described above for the preparation of a pharmaceuticaldosage form for oral administration to a mammal suffering from a fungalinfection, wherein a single such dosage form can be administered oncedaily to said mammal.

Subjects afflicted with a fungal infection that may be treated with thedosage forms described herein include both human subjects and animalsubjects (particularly mammalian subjects such as dogs, cats andrabbits). Disorders with which such subjects may be afflicted includeblastomycosis (pulmonary and extrapulmonary), histoplasmosis (includingchronic cavitary pulmonary disease and disseminated, non-meningealhistoplasmosis), aspergillosis (pulmonary and extrapulmonary),onychomycosis (of the toe-nail and/or fingernail), tinea pedis,dermatophytosis (Ringworm), malessezia/yeast dermatitis, cryptococcosis(“window washers disease), candidiasis, coccidiodomycosis (“valleyfever”), chromoblastomycosis, fungal menigitis, and oral mucositis. Thedosage of itraconazole will vary depending upon factors such as thedisease and severity thereof, the age, weight and condition of thesubject, etc., but in general is between 50 or 100 milligrams per day upto 800 or 1000 milligrams per day.

It has been observed that the tablets of the present invention exhibiteda remarkably lower food-effect than the prior art Sporanox® capsules.This means that the difference between taking the medication after ameal and taking the medication on an empty stomach is significantly lesswhen the tablet of the present invention is administered than whenSporanox® capsules are administered. This is, of course, a hugeadvantage because the medication can be taken at any time during the dayand is no longer dependent upon the intake of a meal.

Moreover, patients who are feeling nauseous or who are not able to eatcan still take the tablets of the present invention.

The accompanying FIGURE and the following examples will serve to furtherillustrate the invention without limiting it.

FIG. 1 shows the DSC thermograms of three different solid dispersionproducts manufactured at different energy input. The top graph relatesto the sample prepared at the highest energy input, the bottom graphrelates to the sample prepared at the lowest energy input. The higherthe energy input during manufacture, the lower the endotherm (J/g)accompanying the endothermic peak in the range of from 240° C. to 250°C.

EXAMPLE 1

A 40/60 (w/w) mixture of itraconazole (21.74 kg) and hydroxypropylmethylcellulose 2910 5 mPa·s (supplied by Janssen and produced by DowChemical in their Midland plant; size distribution as determined usinglaser light diffraction (Malvern Mastersizer) with d_(0.1)=38 μm,d_(0.5)=119 μm, d_(0.5)=256 μm) was sieved and mixed in a planetarymixer until the mixture was homogenous.

This physical mixture of itraconazole and HPMC was fed into a twin screwmelt extruder of the type ZSK 40 (Werner & Pfleiderer) having thefollowing operating parameters: the temperature of the first, second andthird compartment was 20° C., 190° C., and 190° C., respectively, thetemperature of the transitional section was 190° C., the temperature atthe die was 197° C.; the twin screw had a rate of 200 or 250revolutions/min, respectively. The throughput was 22 kg/h.

The extrudate was placed in a hammer mill of type Fitzmill, at 4736 rpmwith a sieve mesh of 0.51 mm. The fraction of particles with a size<125μm was isolated by further sieving through a No. 120 sieve (ASTM E11-70); yield<10%.

A spray-dried mixture of lactose monohydrate (75%) and microcrystallinecellulose (25%) (2.824 kg, 30.57% (w/w)), Crospovidone (784 g, 8.49%(w/w)) Talc (258 g, 2.79% (w/w)), Aerosil (26 g, 0.28% (w/w)), magnesiumstearate (22 g, 0.24% (w/w)) and Sterotex (86 g, 0.093% (w/w)) weresieved and mixed together with the milled extrudate (5 kg, 54.13% (w/w))using a planetary mixer until a homogenous mixture was obtained (15minutes). All (w/w) percentages are based on the total weight of afilm-coated tablet.

The mixture obtained was compressed on a Korsch tabletting machineoperated at a speed of 10,800 tablets/hour and a compression pressure of1500 to 1950 kg/cm² (147-191.1 Mpa). The length of the die was 19 mm,the breadth was 9.5 mm and the radius of the curvature 9.57 mm. Thetablets had the following characteristics: nominal weight: 906.9 mg;maximum height: 5.88 mm; hardness: 11 daN; disintegration time: 2′ 15”;friability: 0%.

The tablets were film-coated using a suspension comprising, by weight,HPMC 2910 5 mPa·s (8.5%), propylene glycol (2.1%), talc (1.7%), and andtitanium dioxide (2.6%) in demineralised water (85%). HPMC 2910 5 mPa·swas added to the purified water and mixed until completely dispersed.The solution was left to stand until clear. Propylene glycol was addedand mixed until uniform. Talc and titanium dioxide were added to thesolution and mixed until uniform. The tablets were placed in a coatingpan and the pigmented coating solution was sprayed onto the cores.

EXAMPLE 2

Multiple batches of itraconazole particles were prepared as set forth inexample 1 (at a twin screw rate of 250 revolutions/min) with thefollowing exceptions. The HPMC was acquired from Colorcon and wasproduced in Dow's Plaquemine plant (d_(0.1)=32 μm, d_(0.5)=92 μm,d_(0.9)=235 μm). The HPMC from this source had a markedly lowerflowability. In view of the lower flowability, the throughput speed hadto be lowered. This resulted in a prolonged transit time of the meltextrudate in the extruder and likely led to a higher energy input. Thethroughput was only 18±3 kg/h. The temperature of the extrusion dies wasincreased to get a smoother extrusion and avoid clogging. Thetemperature of the first, second and third compartment was 20° C., 190°C., and 190° C., respectively, the temperature of the transitionalsection was 205° C., the temperature at the die was 205° C.

Samples of ground extrudates of examples 1 and 2, respectively, weresubjected to DSC analysis and the thermogram between −20° C. and 300° C.was obtained by heating the samples at a temperature rise rate of 10°C./minute. The endothem (J/g) at about 240° C. was determined.

The bioavailability of the tablets was determined according to thefollowing protocol:

Methodology: Open, randomized, 2-way crossover, single oral-dose study,with a 14-day wash-out period in 56 healthy subjects after astandardized breakfast.

Number of subjects: 56 subjects (28 males, 28 females) included,administered and analyzed for safety, 52 included in bioequivalenceevaluation. Diagnosis and main criteria for inclusion: Healthy male andfemale subjects, aged 18-55 years inclusive.

Test product, dose and mode of administration: 200-mg itraconazolemelt-extrusion tablet. Single oral dose of one tablet with 240 mL ofroom temperature non-carbonated water after a standardized breakfast.

Reference product, dose and mode of administration: Sporanox® 100-imgitraconazole capsules, Janssen Ortho LLC. Single oral dose of twocapsules with 240 mL of room temperature non-carbonated water after astandardized breakfast.

Duration of treatment: Two study periods of 36 hours residency in theclinical center {−12 h until 24 h post-dose) with returns to theclinical center for the 36 h, 48 h, 72 h and 96 h blood samplespost-dose, separated by a 14-day wash-out period, single doseadministration during each period.

Statistical methods: Comparison of the pharmacokinetic parameters ofitraconazole and hydroxy-itraconazole obtained after each treatment:ANOVA (model: formulations, subjects, gender, sequences and periods ofadministration) after log transformation.

The analysis of itraconazole and hydroxy itraconazole in human plasmawas performed by HPLC-UV. The extraction method used was derived fromthe method described by Woestenborghs et al.₍(Journal of Chromatography,413 (1987) 332-337). The components were detected by UV-absorption at263 nm. Acquisition was performed using Millennium software of Waters.The 10-points calibration curves were fitted to the model Y=A+B·X using1/X² as weighing factor, where Y is the peak height ratio ofitraconazole or hydroxy-itraconazole and the internal standard, X thenominal calibration level in ng/mL, A the intercept and B the slope.Unknowns were calculated using the formula: X=(Y−A)/B.

The results are summarized in the following table, where the C_(max) andAUC_(t) are given as point estimate in %, relative to the referenceproduct:

Endotherm at Screw speed about 240° C. Bioavailability Example [rpm][J/g] C_(max) AUC_(t) 1 200 0.49 (n = 6) 69.4 76.9 1 250 0.29 (n = 6)82.4 84.3 2 250 0.10 (n = 2) 102.2 116.7

As the above table indicates, a high energy input during melt extrusionproduction leads to improved bioavailability.

We claim:
 1. A method for preparing a solid dispersion productcomprising itraconazole and hydroxypropyl methylcellulose, which methodcomprises: a) blending itraconazole and hydroxypropyl methylcellulose;b) heating the blend to a temperature of 195 to 300° C. so as to obtaina homogenous melt and exerting a shearing and/or kneading action to themelt in an extruder selected from single screw extruders, intermeshingscrew extruders and multi-screw extruders, wherein the screw(s)comprise(s) at least one of reverse-flighted elements, shear elements,kneading discs and rotor blades; c) forcing the thus obtained meltthrough one or more nozzles; d) allowing the melt to solidify to obtaina solid dispersion product; and e) optionally grinding the soliddispersion product; wherein the temperature and the conditions ofshearing and/or kneading in step b) are adjusted such that the soliddispersion product satisfies the formula0.35>ΔH_(tr) wherein ΔH_(tr) represents the endotherm (J/g) accompanyinga transition at an endothermic peak temperature in the range of from240° C. to 250° C.
 2. The method of claim 1, wherein forcing the melt iscarried out at a temperature of 195 to 300° C.
 3. The method of claim 2,additionally comprising compressing the ground solid dispersion productinto a tablet.
 4. The method of claim 1, additionally comprising sievingthe ground solid dispersion product.
 5. The method of claim 1, whereinthe temperature and the conditions of shearing and/or kneading in stepb) are adjusted such that the solid dispersion product satisfies theformula0.20>ΔH_(tr) wherein ΔH_(tr) represents the endotherm (J/g) accompanyinga transition at an endothermic peak temperature in the range of from240° C. to 250° C.
 6. The method of claim 1, wherein the soliddispersion product has a weight-average particle size ranging between 50μm to 600 μm.
 7. The method of claim 1, wherein the total content ofmethoxy and hydroxypropyl groups in the hydroxypropyl methylcellulose isin the range of 23 to 42% by weight.
 8. The method of claim 7, whereinthe methoxy group content is in the range of 19 to 30% by weight and thehydroxypropyl group content is in the range of 4 to 12% by weight. 9.The method of claim 8, wherein the hydroxypropyl methylcellulose has anapparent viscosity of from 3 to 15 mPa·s, as determined as a 2% byweight aqueous solution at 20° C.
 10. The method of claim 1, wherein theweight ratio of itraconazole:hydroxypropyl methylcellulose is in therange of 1:1 to 1:17.
 11. The method of claim 1, wherein the extruderused in step b) is a twin screw extruder.